Taxanes, such as paclitaxel, and other compounds derived from biomass or semi-synthetically have been identified as having significant anticancer properties. Because of the promising clinical activity of certain taxanes (e.g., paclitaxel) against various types of cancer, there is an ongoing need for different methods for preparing paclitaxel and other taxane molecules, including paclitaxel derivatives and analogues. It is believed that the preparation of paclitaxel derivatives and analogues may result in the synthesis of compounds with comparable or greater potency, superior bioavailability, and/or fewer side effects than paclitaxel. Interconversion of one taxane molecule or mixtures of taxane molecules into another taxane molecule is one route to provide various paclitaxel derivatives and analogues for further study of their biological properties.
In addition, the supply and cost of obtaining paclitaxel and other taxane molecules has always been a concern. Three general methods exist for producing paclitaxel. The first is by isolating natural paclitaxel from a biomass source such as Taxus species or from various fermentation broths. The second is by semi-synthesis starting from a related natural taxane compound, and the third is by total synthesis. Only the first two methods are economically viable. The second method can further be divided into multiple approaches depending on the starting taxane compound. In any case, an improved method of producing paclitaxel or other taxanes is of high importance
Murray et al. describe a process for converting taxol A, taxol B, and taxol C to taxol A or docetaxel (U.S. Pat. Nos. 5,679,807 and 5,808,113). The process generally includes reductive deoxygenation of the C-3′ amide group of a fully protected taxane molecule using Schwartz's reagent to form an imine, followed by hydrolysis of the imine to a primary amine. Subsequent acylation of the primary amine with benzoyl chloride or tert-butyloxycarbonyl anhydride can produce taxol A or docetaxel, respectively.
In another example, Kingston et al. describe the conversion of taxol B into paclitaxel by substituting the 2-methyl-2-butenoyl group on the C-13 side chain of taxol B with a benzoyl group (U.S. Pat. No. 5,319,112). The methodology generally includes in sequential order: hydrogenation of the 2-methyl-2-butenoyl group, benzoylation of the C-2′ hydroxyl group, protection of the C-7 hydroxyl group as its trichloroethyloxycarbonyl group, reaction of the C-3′ amide functionality with oxalyl chloride followed by addition of water, reaction with diphenylcarbodiimide to create a free amine at the C-3′ position followed by acyl migration of the benzoyl group from the C-2′ hydroxyl group, and removal of the trichloroethyloxycarbonyl group.
In yet another example, International Application Serial No. PCT/US03/10557 entitled “Conversion of Taxane Molecules,” filed Apr. 5, 2003, describes methods and compositions for reductively deoxygenating an amide group at a C-3′ position of a taxane molecule followed by migration of an acyl group from C-2′ to the C-3′ position. Such methods generally includes the steps of acylating the 2′ hydroxyl; reductively deoxygenating the taxane molecules to form an imine compound; hydrolyzing the imine compound to form a primary amine compound; and then contacting primary amine compound with a base to effect acyl migration.
Thus, there is still a need for other synthetic methodologies for converting taxane molecules into other taxane molecules, which may be more potent anti-cancer compounds. There is also a need for chemical compounds, including taxane molecules, analogs and their intermediates that are useful in the production of paclitaxel or other taxanes.
Accordingly, the present invention is directed to an improved method of converting taxane amides to paclitaxel or other taxanes including, but not limited to, those taxanes listed in FIG. 16. The process of this invention also produces new taxane intermediate compounds, including, but not limited to, taxane amine sulfate salts, that are useful in the production of taxanes.